chr19-6534905-C-G

Variant names:

• chr19-6534905-C-G
• NM_003811.4:c.604C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003811.4(TNFSF9):​c.604C>G​(p.Arg202Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TNFSF9 NM_003811.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.372

Genes affected

TNFSF9 (HGNC:11939): (TNF superfamily member 9) The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This transmembrane cytokine is a bidirectional signal transducer that acts as a ligand for TNFRSF9/4-1BB, which is a costimulatory receptor molecule in T lymphocytes. This cytokine and its receptor are involved in the antigen presentation process and in the generation of cytotoxic T cells. The receptor TNFRSF9/4-1BB is absent from resting T lymphocytes but rapidly expressed upon antigenic stimulation. The ligand encoded by this gene, TNFSF9/4-1BBL, has been shown to reactivate anergic T lymphocytes in addition to promoting T lymphocyte proliferation. This cytokine has also been shown to be required for the optimal CD8 responses in CD8 T cells. This cytokine is expressed in carcinoma cell lines, and is thought to be involved in T cell-tumor cell interaction.[provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053405523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF9	NM_003811.4	c.604C>G	p.Arg202Gly	missense_variant	Exon 3 of 3	ENST00000245817.5	NP_003802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF9	ENST00000245817.5	c.604C>G	p.Arg202Gly	missense_variant	Exon 3 of 3	1	NM_003811.4	ENSP00000245817.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456012 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724338

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.604C>G (p.R202G) alteration is located in exon 3 (coding exon 3) of the TNFSF9 gene. This alteration results from a C to G substitution at nucleotide position 604, causing the arginine (R) at amino acid position 202 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.17
DANN	Benign	0.49
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.36	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.053	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	-0.20	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.27
Sift	Benign	0.62	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.042
MutPred		0.57		Loss of MoRF binding (P = 0.0219);
MVP		0.22
MPC		0.033
ClinPred		0.035	T
GERP RS		-8.4
Varity_R		0.33
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-6534916;